In 1959, while analysing the bacterial flagellar proteins, Ambler and Rees observed an unknown species of amino acid that they eventually identified as methylated lysine. Over half a century later, protein methylation is known to have a regulatory role in many essential cellular processes that range from gene transcription to signal transduction. However, the road to this now burgeoning research field was obstacle-ridden, not least because of the inconspicuous nature of the methyl mark itself. Here, we chronicle the milestone achievements and discuss the future of protein methylation research.
Subscribe to Journal
Get full journal access for 1 year
only $21.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Ambler, R. P. & Rees, M. W. Epsilon-N-methyl-lysine in bacterial flagellar protein. Nature 184, 56–57 (1959).
Neuberger, A. & Sanger, F. The availability of in-acetyl-d-lysine and in-methyl-dl-lysine for growth. Biochem. J. 38, 125–129 (1944).
Neuberger, A. & Sanger, F. The metabolism of lysine. Biochem. J. 38, 119–125 (1944).
Stocker, B. & McDonough, M. A gene determining presence or absence of ɛ-N-methyl-lysine in Salmonella flagellar protein. Nature 189, 556–558 (1961).
Murray, K. The occurrence of epsilon-N-methyl lysine in histones. Biochemistry 3, 10–15 (1964).
Allfrey, V. G., Faulkner, R. & Mirsky, A. E. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc. Natl Acad. Sci. USA 51, 786–794 (1964).
Kim, S. & Paik, W. K. Studies on the origin of epsilon-N-methyl-L-lysine in protein. J. Biol. Chem. 240, 4629–4634 (1965).
Fischer, E. H., Graves, D. J., Crittenden, E. R. & Krebs, E. G. Structure of the site phosphorylated in the phosphorylase b to a reaction. J. Biol. Chem. 234, 1698–1704 (1959).
Phillips, D. M. The presence of acetyl groups of histones. Biochem. J. 87, 258–263 (1963).
Walsh, D. A., Perkins, J. P. & Krebs, E. G. An adenosine 3′,5′-monophosphate-dependant protein kinase from rabbit skeletal muscle. J. Biol. Chem. 243, 3763–3765 (1968).
Burnett, G. & Kennedy, E. P. The enzymatic phosphorylation of proteins. J. Biol. Chem. 211, 969–980 (1954).
Paik, W. K. & Kim, S. Protein methylase I. Purification and properties of the enzyme. J. Biol. Chem. 243, 2108–2114 (1968).
Paik, W. K. & Kim, S. Solubilization and partial purification of protein methylase 3 from calf thymus nuclei. J. Biol. Chem. 245, 6010–6015 (1970).
Liss, M. & Edelstein, L. M. Evidence for the enzymatic methylation of crystalline ovalbumin preparations. Biochem. Biophys. Res. Commun. 26, 497–504 (1967).
Hempel, K. & Lange, H. W. Nɛ-methylated lysine in histones from chicken erythrocytes. Hoppe-Seyler's Z. Physiol. Chem. 349, 603–607 (in German) (1968).
Baldwin, G. S. & Carnegie, P. R. Specific enzymic methylation of an arginine in the experimental allergic encephalomyelitis protein from human myelin. Science 171, 579–581 (1971).
Brostoff, S. & Eylar, E. H. Localization of methylated arginine in the A1 protein from myelin. Proc. Natl Acad. Sci. USA 68, 765–769 (1971).
Kakimoto, Y. & Akazawa, S. Isolation and identification of NG,NG- and NG,N′G-dimethyl-arginine, Nɛ-mono-, di-, and trimethyllysine, and glucosylgalactosyl- and galactosyl-δ-hydroxylysine from human urine. J. Biol. Chem. 245, 5751–5758 (1970).
Kim, S., Benoiton, L. & Paik, W. K. Epsilon-alkyllysinase, purification and properties of the enzyme. J. Biol. Chem. 239, 3790–3796 (1964).
Paik, W. K. & Kim, S. Enzymatic demethylation of calf thymus histones. Biochem. Biophys. Res. Commun. 51, 781–788 (1973).
Duerre, J. A. & Lee, C. T. In vivo methylation and turnover of rat brain histones. J. Neurochem. 23, 541–547 (1974).
Byvoet, P., Shepherd, G. R., Hardin, J. M. & Noland, B. J. The distribution and turnover of labeled methyl groups in histone fractions of cultured mammalian cells. Arch. Biochem. Biophys. 148, 558–567 (1972).
Stallcup, M. R. Role of protein methylation in chromatin remodeling and transcriptional regulation. Oncogene 20, 3014–3020 (2001).
Calnan, B. J., Tidor, B., Biancalana, S., Hudson, D. & Frankel, A. D. Arginine-mediated RNA recognition: the arginine fork. Science 252, 1167–1171 (1991).
Najbauer, J., Johnson, B. A., Young, A. L. & Aswad, D. W. Peptides with sequences similar to glycine, arginine-rich motifs in proteins interacting with RNA are efficiently recognized by methyltransferase(s) modifying arginine in numerous proteins. J. Biol. Chem. 268, 10501–10509 (1993).
Clarke, S. Protein methylation. Curr. Opin. Cell Biol. 5, 977–983 (1993).
Orlando, V. Mapping chromosomal proteins in vivo by formaldehyde-crosslinked-chromatin immunoprecipitation. Trends Biochem. Sci. 25, 99–104 (2000).
Solomon, M. J., Larsen, P. L. & Varshavsky, A. Mapping protein-DNA interactions in vivo with formaldehyde: evidence that histone H4 is retained on a highly transcribed gene. Cell 53, 937–947 (1988).
Brownell, J. E. et al. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation. Cell 84, 843–851 (1996).
Taunton, J., Hassig, C. A. & Schreiber, S. L. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272, 408–411 (1996).
Klein, R. R. & Houtz, R. L. Cloning and developmental expression of pea ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit N-methyltransferase. Plant Mol. Biol. 27, 249–261 (1995).
Henry, M. F. & Silver, P. A. A novel methyltransferase (Hmt1p) modifies poly(A)+-RNA-binding proteins. Mol. Cell. Biol. 16, 3668–3678 (1996).
Lin, W. J., Gary, J. D., Yang, M. C., Clarke, S. & Herschman, H. R. The mammalian immediate-early TIS21 protein and the leukemia-associated BTG1 protein interact with a protein-arginine N-methyltransferase. J. Biol. Chem. 271, 15034–15044 (1996).
Shen, E. C. et al. Arginine methylation facilitates the nuclear export of hnRNP proteins. Genes Dev. 12, 679–691 (1998).
Chen, D. et al. Regulation of transcription by a protein methyltransferase. Science 284, 2174–2177 (1999).
Strahl, B. D., Ohba, R., Cook, R. G. & Allis, C. D. Methylation of histone H3 at lysine 4 is highly conserved and correlates with transcriptionally active nuclei in Tetrahymena. Proc. Natl Acad. Sci. USA 96, 14967–14972 (1999).
Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000).
Herz, H. M., Garruss, A. & Shilatifard, A. SET for life: biochemical activities and biological functions of SET domain-containing proteins. Trends Biochem. Sci. 38, 621–639 (2013).
Zhang, X., Zhou, L. & Cheng, X. Crystal structure of the conserved core of protein arginine methyltransferase PRMT3. EMBO J. 19, 3509–3519 (2000).
Weiss, V. H. et al. The structure and oligomerization of the yeast arginine methyltransferase, Hmt1. Nat. Struct. Biol. 7, 1165–1171 (2000).
Greer, E. L. & Shi, Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat. Rev. Genet. 13, 343–357 (2012).
Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000).
Lee, J. S., Smith, E. & Shilatifard, A. The language of histone crosstalk. Cell 142, 682–685 (2010).
Lachner, M., O'Carroll, D., Rea, S., Mechtler, K. & Jenuwein, T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116–120 (2001).
Bannister, A. J. et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410, 120–124 (2001).
Nielsen, P. R. et al. Structure of the HP1 chromodomain bound to histone H3 methylated at lysine 9. Nature 416, 103–107 (2002).
Jacobs, S. A. & Khorasanizadeh, S. Structure of HP1 chromodomain bound to a lysine 9-methylated histone H3 tail. Science 295, 2080–2083 (2002).
Taverna, S. D., Li, H., Ruthenburg, A. J., Allis, C. D. & Patel, D. J. How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat. Struct. Mol. Biol. 14, 1025–1040 (2007).
Musselman, C. A., Lalonde, M. E., Cote, J. & Kutateladze, T. G. Perceiving the epigenetic landscape through histone readers. Nat. Struct. Mol. Biol. 19, 1218–1227 (2012).
Patel, D. J. & Wang, Z. Readout of epigenetic modifications. Annu. Rev. Biochem. 82, 81–118 (2013).
Vermeulen, M. et al. Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4. Cell 131, 58–69 (2007).
Nielsen, S. J. et al. Rb targets histone H3 methylation and HP1 to promoters. Nature 412, 561–565 (2001).
Bannister, A. J., Schneider, R. & Kouzarides, T. Histone methylation: dynamic or static? Cell 109, 801–806 (2002).
Ahmad, K. & Henikoff, S. The histone variant H3.3 marks active chromatin by replication-independent nucleosome assembly. Mol. Cell 9, 1191–1200 (2002).
Allis, C. D., Bowen, J. K., Abraham, G. N., Glover, C. V. & Gorovsky, M. A. Proteolytic processing of histone H3 in chromatin: a physiologically regulated event in Tetrahymena micronuclei. Cell 20, 55–64 (1980).
Humphrey, G. W. et al. Stable histone deacetylase complexes distinguished by the presence of SANT domain proteins CoREST/kiaa0071 and Mta-L1. J. Biol. Chem. 276, 6817–6824 (2001).
Shi, Y. et al. Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature 422, 735–738 (2003).
Tong, J. K., Hassig, C. A., Schnitzler, G. R., Kingston, R. E. & Schreiber, S. L. Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex. Nature 395, 917–921 (1998).
You, A., Tong, J. K., Grozinger, C. M. & Schreiber, S. L. CoREST is an integral component of the CoREST- human histone deacetylase complex. Proc. Natl Acad. Sci. USA 98, 1454–1458 (2001).
Hakimi, M. A. et al. A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes. Proc. Natl Acad. Sci. USA 99, 7420–7425 (2002).
Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004).
Metzger, E. et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437, 436–439 (2005).
Tsukada, Y. et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811–816 (2006).
Whetstine, J. R. et al. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 125, 467–481 (2006).
Fodor, B. D. et al. Jmjd2b antagonizes H3K9 trimethylation at pericentric heterochromatin in mammalian cells. Genes Dev. 20, 1557–1562 (2006).
Cloos, P. A. et al. The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature 442, 307–311 (2006).
Kooistra, S. M. & Helin, K. Molecular mechanisms and potential functions of histone demethylases. Nat. Rev. Mol. Cell Biol. 13, 297–311 (2012).
Brahms, H., Meheus, L., de Brabandere, V., Fischer, U. & Luhrmann, R. Symmetrical dimethylation of arginine residues in spliceosomal Sm protein B/B' and the Sm-like protein LSm4, and their interaction with the SMN protein. RNA 7, 1531–1542 (2001).
Friesen, W. J., Massenet, S., Paushkin, S., Wyce, A. & Dreyfuss, G. SMN, the product of the spinal muscular atrophy gene, binds preferentially to dimethylarginine-containing protein targets. Mol. Cell 7, 1111–1117 (2001).
Yu, M. C. et al. Arginine methyltransferase affects interactions and recruitment of mRNA processing and export factors. Genes Dev. 18, 2024–2035 (2004).
Li, H. et al. Lipopolysaccharide-induced methylation of HuR, an mRNA-stabilizing protein, by CARM1. Coactivator-associated arginine methyltransferase. J. Biol. Chem. 277, 44623–44630 (2002).
Nishida, K. M. et al. Functional involvement of Tudor and dPRMT5 in the piRNA processing pathway in Drosophila germlines. EMBO J. 28, 3820–3831 (2009).
Reuter, M. et al. Loss of the Mili-interacting Tudor domain-containing protein-1 activates transposons and alters the Mili-associated small RNA profile. Nat. Struct. Mol. Biol. 16, 639–646 (2009).
Vagin, V. V. et al. Proteomic analysis of murine Piwi proteins reveals a role for arginine methylation in specifying interaction with Tudor family members. Genes Dev. 23, 1749–1762 (2009).
Chen, C., Nott, T. J., Jin, J. & Pawson, T. Deciphering arginine methylation: Tudor tells the tale. Nat. Rev. Mol. Cell Biol. 12, 629–642 (2011).
Clarke, S. G. Protein methylation at the surface and buried deep: thinking outside the histone box. Trends Biochem. Sci. 38, 243–252 (2013).
Pahlich, S., Zakaryan, R. P. & Gehring, H. Protein arginine methylation: cellular functions and methods of analysis. Biochim. Biophys. Acta 1764, 1890–1903 (2006).
Chuikov, S. et al. Regulation of p53 activity through lysine methylation. Nature 432, 353–360 (2004).
Huang, J. et al. Repression of p53 activity by Smyd2- mediated methylation. Nature 444, 629–632 (2006).
Shi, X. et al. Modulation of p53 function by SET8-mediated methylation at lysine 382. Mol. Cell 27, 636–646 (2007).
Huang, J. et al. G9a and Glp methylate lysine 373 in the tumor suppressor p53. J. Biol. Chem. 285, 9636–9641 (2010).
Jansson, M. et al. Arginine methylation regulates the p53 response. Nat. Cell Biol. 10, 1431–1439 (2008).
Metzger, E. et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437, 436–439 (2005).
Huszar, G. & Elzinga, M. Epsilon-N-methyl lysine in myosin. Nature 223, 834–835 (1969).
DeLange, R. J., Glazer, A. N. & Smith, E. L. Presence and location of an unusual amino acid, epsilon-N-trimethyllysine, in cytochrome c of wheat germ and Neurospora. J. Biol. Chem. 244, 1385–1388 (1969).
Pollack, B. P. et al. The human homologue of the yeast proteins Skb1 and Hsl7p interacts with Jak kinases and contains protein methyltransferase activity. J. Biol. Chem. 274, 31531–31542 (1999).
Ong, S. E., Mittler, G. & Mann, M. Identifying and quantifying in vivo methylation sites by heavy methyl SILAC. Nat. Methods 1, 119–126 (2004).
Levy, D. et al. A proteomic approach for the identification of novel lysine methyltransferase substrates. Epigenetics Chromatin 4, 19 (2011).
Cao, X. J., Arnaudo, A. M. & Garcia, B. A. Large-scale global identification of protein lysine methylation in vivo. Epigenetics 8, 477–485 (2013).
Guo, A. et al. Immunoaffinity enrichment and mass spectrometry analysis of protein methylation. Mol. Cell. Proteomics 13, 372–387 (2014).
Liu, H. et al. A method for systematic mapping of protein lysine methylation identifies functions for HP1beta in DNA damage response. Mol. Cell 50, 723–735 (2013).
Moore, K. E. et al. A general molecular affinity strategy for global detection and proteomic analysis of lysine methylation. Mol. Cell 50, 444–456 (2013).
Islam, K. et al. Bioorthogonal profiling of protein methylation using azido derivative of S-adenosyl-L-methionine. J. Am. Chem. Soc. 134, 5909–5915 (2012).
Islam, K. et al. Defining efficient enzyme-cofactor pairs for bioorthogonal profiling of protein methylation. Proc. Natl Acad. Sci. USA 110, 16778–16783 (2013).
Binda, O. et al. A chemical method for labeling lysine methyltransferase substrates. Chembiochem 12, 330–334 (2011).
Peters, W. et al. Enzymatic site-specific functionalization of protein methyltransferase substrates with alkynes for click labeling. Angew. Chem. Int. Ed. 49, 5170–5173 (2010).
Biggar, K. K. & Li, S. S. Non-histone protein methylation as a regulator of cellular signalling and function. Nat. Rev. Mol. Cell Biol. 16, 5–17 (2015).
Andreu-Perez, P. et al. Protein arginine methyltransferase 5 regulates ERK1/2 signal transduction amplitude and cell fate through CRAF. Sci. Signal. 4, ra58 (2011).
Mazur, P. K. et al. SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer. Nature 510, 283–287 (2014).
Bikkavilli, R. K. et al. Dishevelled3 is a novel arginine methyl transferase substrate. Sci. Rep. 2, 805 (2012).
Kim, E. et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell 23, 839–852 (2013).
Levy, D. et al. Lysine methylation of the NF-kappaB subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-kappaB signaling. Nat. Immunol. 12, 29–36 (2011).
Kubicek, S. et al. Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol. Cell 25, 473–481 (2007).
Tachibana, M. et al. Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9. Genes Dev. 19, 815–826 (2005).
Rathert, P. et al. Protein lysine methyltransferase G9a acts on non-histone targets. Nat. Chem. Biol. 4, 344–346 (2008).
Kaniskan, H. U., Konze, K. D. & Jin, J. Selective inhibitors of protein methyltransferases. J. Med. Chem. 58, 1596–1629 (2015).
Ferguson, A. D. et al. Structural basis of substrate methylation and inhibition of SMYD2. Structure 19, 1262–1273 (2011).
Saddic, L. A. et al. Methylation of the retinoblastoma tumor suppressor by SMYD2. J. Biol. Chem. 285, 37733–37740 (2010).
Castillo-Aguilera, O., Depreux, P., Halby, L., Arimondo, P. B. & Goossens, L. DNA methylation targeting: the DNMT/HMT crosstalk challenge. Biomolecules 7, E3 (2017).
Chan-Penebre, E. et al. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat. Chem. Biol. 11, 432–437 (2015).
Okada, Y. et al. hDOT1L links histone methylation to leukemogenesis. Cell 121, 167–178 (2005).
Daigle, S. R. et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 20, 53–65 (2011).
Daigle, S. R. et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood 122, 1017–1025 (2013).
Cao, R. et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 1039–1043 (2002).
Morin, R. D. et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat. Genet. 42, 181–185 (2010).
Kleer, C. G. et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl Acad. Sci. USA 100, 11606–11611 (2003).
Varambally, S. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002).
Sneeringer, C. J. et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc. Natl Acad. Sci. USA 107, 20980–20985 (2010).
Knutson, S. K. et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat. Chem. Biol. 8, 890–896 (2012).
Knutson, S. K. et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol. Cancer Ther. 13, 842–854 (2014).
Liu, F. et al. Exploiting an allosteric binding site of PRMT3 yields potent and selective inhibitors. J. Med. Chem. 56, 2110–2124 (2013).
Kaniskan, H. U. et al. A potent, selective and cell-active allosteric inhibitor of protein arginine methyltransferase 3 (PRMT3). Angew. Chem. Int. Ed. 54, 5166–5170 (2015).
Lee, M. G., Wynder, C., Schmidt, D. M., McCafferty, D. G. & Shiekhattar, R. Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications. Chem. Biol. 13, 563–567 (2006).
Schmidt, D. M. & McCafferty, D. G. trans-2-phenylcyclopropylamine is a mechanism-based inactivator of the histone demethylase LSD1. Biochemistry 46, 4408–4416 (2007).
Binda, C. et al. Biochemical, structural, and biological evaluation of tranylcypromine derivatives as inhibitors of histone demethylases LSD1 and LSD2. J. Am. Chem. Soc. 132, 6827–6833 (2010).
Yang, M. et al. Structural basis for the inhibition of the LSD1 histone demethylase by the antidepressant trans-2-phenylcyclopropylamine. Biochemistry 46, 8058–8065 (2007).
Schenk, T. et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat. Med. 18, 605–611 (2012).
Harris, W. J. et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell 21, 473–487 (2012).
Morera, L., Lubbert, M. & Jung, M. Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy. Clin. Epigenetics 8, 57 (2016).
Kruidenier, L. et al. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 488, 404–408 (2012).
Hancock, R. L., Dunne, K., Walport, L. J., Flashman, E. & Kawamura, A. Epigenetic regulation by histone demethylases in hypoxia. Epigenomics 7, 791–811 (2015).
Teperino, R., Schoonjans, K. & Auwerx, J. Histone methyl transferases and demethylases; can they link metabolism and transcription? Cell Metab. 12, 321–327 (2010).
Shyh-Chang, N. et al. Influence of threonine metabolism on S-adenosylmethionine and histone methylation. Science 339, 222–226 (2013).
Ulanovskaya, O. A., Zuhl, A. M. & Cravatt, B. F. NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. Nat. Chem. Biol. 9, 300–306 (2013).
Mentch, S. J. et al. Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism. Cell Metab. 22, 861–873 (2015).
Carey, B. W., Finley, L. W., Cross, J. R., Allis, C. D. & Thompson, C. B. Intracellular alpha-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature 518, 413–416 (2015).
Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).
Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009).
Ward, P. S. et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17, 225–234 (2010).
Hino, S. et al. FAD-dependent lysine-specific demethylase-1 regulates cellular energy expenditure. Nat. Commun. 3, 758 (2012).
Luka, Z., Mudd, S. H. & Wagner, C. Glycine N-methyltransferase and regulation of S-adenosylmethionine levels. J. Biol. Chem. 284, 22507–22511 (2009).
Xiao, M. et al. Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 26, 1326–1338 (2012).
Olsen, J. B. et al. Quantitative profiling of the activity of protein lysine methyltransferase SMYD2 using SILAC-based proteomics. Mol. Cell. Proteomics 15, 892–905 (2016).
Zee, B. M. & Garcia, B. A. Discovery of lysine post-translational modifications through mass spectrometric detection. Essays Biochem. 52, 147–163 (2012).
Ostareck-Lederer, A. et al. Asymmetric arginine dimethylation of heterogeneous nuclear ribonucleoprotein K by protein-arginine methyltransferase 1 inhibits its interaction with c-Src. J. Biol. Chem. 281, 11115–11125 (2006).
Vermeulen, M. et al. Quantitative interaction proteomics and genome-wide profiling of epigenetic histone marks and their readers. Cell 142, 967–980 (2010).
Hu, S. B. et al. Protein arginine methyltransferase CARM1 attenuates the paraspeckle-mediated nuclear retention of mRNAs containing IRAlus. Genes Dev. 29, 630–645 (2015).
Castello, A. et al. Comprehensive identification of RNA-binding domains in human cells. Mol. Cell 63, 696–710 (2016).
Beaver, J. E. & Waters, M. L. Molecular recognition of Lys and Arg methylation. ACS Chem. Biol. 11, 643–653 (2016).
Barth, T. K. & Imhof, A. Fast signals and slow marks: the dynamics of histone modifications. Trends Biochem. Sci. 35, 618–626 (2010).
Zee, B. M., Levin, R. S., Dimaggio, P. A. & Garcia, B. A. Global turnover of histone post-translational modifications and variants in human cells. Epigenetics Chromatin 3, 22 (2010).
Jacobs, S. A. et al. The active site of the SET domain is constructed on a knot. Nat. Struct. Biol. 9, 833–838 (2002).
Min, J., Zhang, X., Cheng, X., Grewal, S. I. & Xu, R. M. Structure of the SET domain histone lysine methyltransferase Clr4. Nat. Struct. Biol. 9, 828–832 (2002).
Trievel, R. C., Beach, B. M., Dirk, L. M., Houtz, R. L. & Hurley, J. H. Structure and catalytic mechanism of a SET domain protein methyltransferase. Cell 111, 91–103 (2002).
Wilson, J. R. et al. Crystal structure and functional analysis of the histone methyltransferase SET7/9. Cell 111, 105–115 (2002).
Zhang, X. et al. Structure of the Neurospora SET domain protein DIM-5, a histone H3 lysine methyltransferase. Cell 111, 117–127 (2002).
Lu, X. et al. The effect of H3K79 dimethylation and H4K20 trimethylation on nucleosome and chromatin structure. Nat. Struct. Mol. Biol. 15, 1122–1124 (2008).
Pasini, D. et al. Characterization of an antagonistic switch between histone H3 lysine 27 methylation and acetylation in the transcriptional regulation of Polycomb group target genes. Nucleic Acids Res. 38, 4958–4969 (2010).
Tie, F. et al. CBP-mediated acetylation of histone H3 lysine 27 antagonizes Drosophila Polycomb silencing. Development 136, 3131–3141 (2009).
The authors thank L. Sawyer for help with retrieving information and materials relating to Richard Ambler's research; P. Hornbeck for help with the analyses of known methylated proteins; O. Gozani, J. Olsen and B. Fischer for discussions; and M. Teplova for help with the figures. Work in the laboratory of Y.S. is supported by the US National Institutes of Health (CA118487, GM117264 and MH096066) and Boston Children's Hospital. Y.S. is an American Cancer Society Research Professor. The authors apologize to colleagues whose work could not be cited owing to space limitations.
Y.S. is a co-founder of Constellation Pharmaceuticals, Inc., Cambridge, Massachusetts, USA, and is a member of its scientific advisory board. Y.S. is also a consultant for Active Motif, Carlsbad, California, USA.
About this article
Cite this article
Murn, J., Shi, Y. The winding path of protein methylation research: milestones and new frontiers. Nat Rev Mol Cell Biol 18, 517–527 (2017). https://doi.org/10.1038/nrm.2017.35
Integrating Top-Down and Bottom-Up Mass Spectrometric Strategies for Proteomic Profiling of Iranian Saw-Scaled Viper, Echis carinatus sochureki, Venom
Journal of Proteome Research (2021)
Tau Post-translational Modifications: Dynamic Transformers of Tau Function, Degradation, and Aggregation
Frontiers in Neurology (2021)
Journal of Biological Chemistry (2021)
ACS Chemical Biology (2021)
Journal of Molecular Biology (2021)